title: Apolipoprotein E isoform-dependent microglia migration.
abstract: Complement component C5a and ATP are potent effectors of microglial movement and are increased in diverse neurodegenerative diseases and at sites of injury. Apolipoprotein E (apoE) influences microglial function, and different human apoE isoforms confer variable risk for development of neurodegenerative disorders, especially Alzheimer's disease. The purpose of this investigation was to test the hypothesis that mouse apoE and human apoE isoforms influence microglial migration. Using primary wild-type and apoE-deficient microglia, we show that C5a- and ATP-stimulated chemotaxis are largely apoE-dependent processes with different molecular bases. Although the C5a-dependent chemotaxis of wild-type microglia was completely blocked by receptor-associated protein (RAP), suggesting apoE receptor involvement, ATP-stimulated migration was unaffected by RAP but was associated with differential ERK phosphorylation. Studies using primary microglia derived from targeted replacement mice "humanized" for the coding exons (protein isoform) of human ε2 (apoE2), ε3 (apoE3), or ε4 (apoE4) allele of APOE revealed that primary mouse microglia expressing apoE4 or apoE2 exhibited significantly reduced C5a- and ATP-stimulated migration compared with microglia expressing human apoE3. This study, for the first time, demonstrates apoE dependence and apoE isoform-specific modulation of microglial migration in response to distinct chemotactic stimuli commonly associated with neurodegenerative disease.
authors.affiliation: Department of Pathology, Neuropathology Division, University of Washington, Seattle, Washington, USA.
authors.forename: Eiron
authors.initials: E
authors.lastname: Cudaback
authors.forename: Xianwu
authors.initials: X
authors.lastname: Li
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Montine
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.forename: C Dirk
authors.initials: CD
authors.lastname: Keene
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D002633:Chemotaxis; D005786:Gene Expression Regulation / Q000502:physiology; D005838:Genotype; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D020033:Protein Isoforms
chemical_list: D001057:Apolipoproteins E; D020033:Protein Isoforms